Multisite rTMS combined with cognitive training modulates effective connectivity in patients with Alzheimer's disease.

Purpose: To investigate the effective connectivity (EC) changes after multisite repetitive transcranial magnetic stimulation (rTMS) combined with cognitive training (COG).

Method: We selected 51 patients with mild or moderate Alzheimer's disease (AD) and delivered 10 Hz rTMS over the left dorsal lateral prefrontal cortex (DLPFC) and the lateral temporal lobe (LTL) combined with COG or sham stimulation for 4 weeks. The selected AD patients were divided into real (real rTMS+COG, = 11) or sham (sham rTMS+COG, = 8) groups to undergo neuropsychological assessment, resting-state fMRI, and 3D brain structural imaging before (T0), immediately at the end of treatment (T4), and 4 weeks after treatment (T8). A 2 × 3 factorial design with "time" as the within-subjects factor (three levels: T0, T4, and T8) and "group" as the between-subjects factor (two levels: real and sham) was used to investigate the EC changes related to the stimulation targets in the rest of the brain, as well as the causal interactions among seven resting-state networks based on Granger causality analysis (GCA).

Results: At the voxel level, the EC changes from the left DLPFC out to the left inferior parietal lobe and the left superior frontal gyrus, as well as from the left LTL out to the left orbital frontal cortex, had a significant group × time interaction effect. At the network level, a significant interaction effect was identified in the increase in EC from the limbic network out to the default mode network. The decrease in EC at the voxel level and the increase in EC at the network level were both associated with the improved ability to perform activities of daily living and cognitive function.

Conclusion: Multisite rTMS combined with cognitive training can modulate effective connectivity in patients with AD, resulting in improved ability to perform activities of daily living and cognitive function.